Mammalian cells in vivo integrate and respond to cues in their microenvironment that vary in both time and space. In particular, interactions between neighboring cells can regulate both the fate and function of individual cells as well as govern the emergent properties of the resultant tissue. Because such cell-cell interactions occur primarily through direct contact or exchange of soluble factors, understanding the temporal and spatial aspects of these signals is of fundamental importance to tissue biology. Recent advances in cell ‘micropatterning’ have already proven invaluable in increasing our understanding of the structure-function relationships of such multicellular communities (El-Ali, J., Sorger, P. K. & Jensen, K. F. (2006) Nature 442, 403-11; Bhatia, S. N., Balis, U. J., Yarmush, M. L. & Toner, M. (1999) Faseb J 13, 1883-900; Nelson, C. M., Jean, R. P., Tan, J. L., Liu, W. F., Sniadecki, N. J., Spector, A. A. & Chen, C. S. (2005) Proc Natl Acad Sci USA 102, 11594-9; and Liu, W. F., Nelson, C. M., Pirone, D. M. & Chen, C. S. (2006) J. Cell Biol. 173, 431-441). However, dynamic manipulation of tissue structure in vitro has remained largely out of reach.
Previous efforts towards spatio-temporal control of tissue organization at the cellular scale have focused on modulation of the adhesive properties of the culture substrate (Okano, T., Yamada, N., Okuhara, M., Sakai, H. & Sakurai, Y. (1995) Biomaterials 16, 297-303; Lahann, J., Mitragotri, S., Tran, T. N., Kaido, H., Sundaram, J., Choi, I. S., Hoffer, S., Somorjai, G. A. & Langer, R. (2003) Science 299, 371-4; and Jiang, X., Ferrigno, R., Mrksich, M. & Whitesides, G. M. (2003) J Am Chem Soc 125, 2366-7.). Through the micropatterning of surface chemistries that can be dynamically altered, localized attachment and release of cells has been demonstrated (Cheng, X. H., Wang, Y. B., Hanein, Y., Bohringer, K. F. & Ratner, B. D. (2004) Journal of Biomedical Materials Research Part A 70A, 159-168; and Yeo, W. S., Yousaf, M. N. & Mrksich, M. (2003) J Am Chem Soc 125, 14994-5). Nonetheless, these manipulations are typically not reversible (i.e., nonadhesive surfaces are rendered adhesive just once), they do not allow the decoupling of processes associated with adhesion from those correlated with cell-cell interaction (i.e., attachment, spreading, and contact with neighboring cells have overlapping time scales), nor can these platforms accommodate serial manipulations to mimic key biological events (i.e., sequential exposure of a target cell population to different inducer populations). Manipulations of surface chemistry are also limited by the inability to precisely control tissue composition: sequential seeding of different cell types can result in contamination of pure populations and maintaining micron-scale proximity of two cell populations in the absence of contact over many days—important for decoupling the relative role of contact and paracrine signals—has not been achieved.